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Robust Distal Tip Cell Pathfinding in the Face of Temperature Stress Is GENETICS | INVESTIGATION Robust Distal Tip Cell Pathfinding in the Face of Temperature Stress Is Ensured by Two Conserved microRNAS in Caenorhabditis elegans Samantha L. Burke,* Molly Hammell,† and Victor Ambros*,1 *Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and †Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 ABSTRACT Biological robustness, the ability of an organism to maintain a steady-state output as genetic or environmental inputs change, is critical for proper development. MicroRNAs have been implicated in biological robustness mechanisms through their post- transcriptional regulation of genes and gene networks. Previous research has illustrated examples of microRNAs promoting robustness as part of feedback loops and genetic switches and by buffering noisy gene expression resulting from environmental and/or internal changes. Here we show that the evolutionarily conserved microRNAs mir-34 and mir-83 (homolog of mammalian mir-29) contribute to the robust migration pattern of the distal tip cells in Caenorhabditis elegans by specifically protecting against stress from temperature changes. Furthermore, our results indicate that mir-34 and mir-83 may modulate the integrin signaling involved in distal tip cell migration by potentially targeting the GTPase cdc-42 and the beta-integrin pat-3. Our findings suggest a role for mir-34 and mir- 83 in integrin-controlled cell migrations that may be conserved through higher organisms. They also provide yet another example of microRNA-based developmental robustness in response to a specific environmental stress, rapid temperature fluctuations. KEYWORDS mir-34; mir-83; mir-29; distal tip cell migrations; robustness HE ability of a living system to maintain a steady-state as stage-specific diapause (Baugh and Sternberg 2006; Fu- Toutput in the face of environmental and physiological kuyama et al. 2006; Ruaud and Bessereau 2006; Schindler stresses is referred to as biological robustness (Kitano 2004). et al. 2014) and proceeding to the dauer larvae stage, an Organisms must be able to compensate for adverse changes alternative third larval stage that allows C. elegans to in gene expression caused by environmental stresses and lengthen their lifespan and survive food deprivation or heat internal gene expression noise if development is to proceed stress (Cassada and Russell 1975; Liu et al. 1995). unchanged. The nematode Caenorhabditis elegans is a useful MicroRNAs (miRNAs) are single-stranded RNAs of 22 model for studying such robustness. C. elegans development nucleotides that negatively regulate the translation of their has been mapped to a cell-by-cell level, such that we know target messenger RNAs (mRNAs) by binding to their 39 un- exactly when cell divisions occur and what the fate of each translated region (39 UTR) as part of a protein–RNA com- cell is (Sulston 1976; Sulston and Horvitz 1977; Kimble and plex called the miRNA-induced silencing complex (miRISC). Hirsh 1979; Sulston et al. 1983). There is also extensive Target recognition is determined by the miRNA’s seed se- research on the worm’s responses to stress, including quence, nucleotides two through seven (reviewed in Ambros stress-induced alternative larval developmental choices such 2004; Bartel 2004). miRNAs with the same seed sequence can presumably regulate the same target mRNAs and are grouped together within a miRNA family (reviewed in Bartel Copyright © 2015 by the Genetics Society of America doi: 10.1534/genetics.115.179184 2009). In addition to being regulated by multiple members Manuscript received March 12, 2015; accepted for publication June 10, 2015; of a miRNA family, an mRNA can be cotargeted by multiple published Early Online June 15, 2015. distinct miRNAs families, if it contains the corresponding Available freely online through the author-supported open access option. Supporting information is available online at www.genetics.org/lookup/suppl/ distinct seed-complementary sites. Such interfamily and doi:10.1534/genetics.115.179184/-/DC1. intrafamily cotargeting is considered one reason why 1Corresponding author: Program in Molecular Medicine, Biotech Two, Suite 306, 373 Plantation St., University of Massachusetts Medical School, Worcester, MA 01605. most single miRNA gene deletion mutants in C. elegans do E-mail: [email protected] not display apparent phenotypes; although one negative Genetics, Vol. 200, 1201–1218 August 2015 1201 regulator is deleted, the target mRNAs in question remain mir-83(n4638); mir-34(gk437) mutants have a decreased under the regulation of additional, functionally redundant lifespan and decreased fecundity, suggesting that the loss miRNAs (Miska et al. 2007; Alvarez-Saavedra and Horvitz of these two miRNAs has repercussions for the biological 2010). Findings reported by the Abbott lab exemplified this fitness of the animals. phenomenon (Brenner et al. 2010). They screened for de- velopmental phenotypes resulting from miRNA deletions in Materials and Methods genetically sensitized backgrounds, in which the miRNA- specific argonaute protein alg-1 was no longer functional. C. elegans strains In the alg-1 mutant background, overall miRNA production The C. elegans Bristol N2 strain was used as wild type in the is partially compromised, such that the additional deletion study (Brenner 1974). Additional strains are listed in Table of an otherwise redundant single miRNA can result in target S2. Both the n4638 and gk437 alleles were backcrossed to deregulation and visible phenotypes. N2 four times upon receipt. The VT2595 strain was used as In their study, the Abbott lab members identified six the mir-83(n4638); mir-34(gk437) double mutant except miRNAs involved in gonad morphogenesis (Brenner et al. when VT3289 is explicitly discussed in Figure 2C. 2010), a normally robust developmental process that is de- pendent on the migration of two distal tip cells (DTCs) C. elegans maintenance (reviewed in Wong and Schwarzbauer 2012). One of these Strains were maintained using standard procedures on miRNAs included mir-83, a miRNA that is highly conserved nematode growth media (NGM) plates seeded with Escher- in animals, including mammals (known as mir-29, Support- ichia coli strain HB101 (Brenner 1974), unless explicitly ing Information, Figure S1) (Lagos-Quintana et al. 2001, stated as being raised on OP50. Strains were raised at 20° 2002; Lau 2001; Mourelatos et al. 2002; Dostie et al. unless otherwise stated when temperature was oscillated. 2003; Lim et al. 2003; Lim 2003; Michael et al. 2003; Suh et al. 2004; Poy et al. 2004; Landgraf et al. 2007; Lui et al. Sequence alignments, target prediction, and fi 2007). Mammalian mir-29 has been previously implicated in statistical signi cance regulating cellular proliferation, differentiation, apoptosis, MicroRNA sequences were supplied by miRBase (Lagos- and the extracellular matrix (reviewed in Boominathan Quintana et al. 2001; Lau 2001; Lagos-Quintana et al. 2010; Kriegel et al. 2012). To better understand how mir-83 2002; Mourelatos et al. 2002; Ambros et al. 2003; Aravin functions, we set out to determine its mRNA targets and et al. 2003; Dostie et al. 2003; Grad et al. 2003; Houbaviy miRNA coregulators in C. elegans. Using mirWIP (Hammell et al. 2003; Lim et al. 2003; Lim 2003; Michael et al. 2003; et al. 2008), we noticed an overlap between the predicted Sempere et al. 2003; Griffiths-Jones 2004; Poy et al. 2004; mRNA targets for mir-83 and mir-34, another miRNA that is Suh et al. 2004; Griffiths-Jones et al. 2006, 2008; Landgraf conserved between nematodes and mammals (Figure S1, Ta- et al. 2007; Lui et al. 2007; Kozomara and Griffiths-Jones ble S1) (Lau 2001; Ambros et al. 2003; Grad et al. 2003; 2011, 2014) and aligned by eye. Predicted targets were Houbaviy et al. 2003; Lim et al. 2003; Lim 2003; Landgraf identified using mirWIP (Hammell et al. 2008). Throughout et al. 2007). mir-34 has been shown to have tumor suppressor the manuscript, three significance asterisks (***) are used activity in mammalian systems. There, its transcription is ac- for a P-value of #0.005, two (**) for a P-value .0.005 and tivated by p53 and it functions to reinforce p53 negative reg- #0.01, and one (*) for a P-value .0.01 and #0.05. ulation (reviewed in He et al. 2007; Yamakuchi and Migration defective phenotype scoring Lowenstein 2009; Hermeking 2009; Rokavec et al. 2014). To further understand the roles of mir-83 and mir-34,we Hypochlorite treatment (Stiernagle 2006) was used to iso- tested for genetic redundancy by creating the double mutant late embryos. Where noted, synchronized populations were and looking at developmental phenotypes. We also identi- created by allowing embryos to hatch in M9 buffer for 24 fied potential targets of mir-34 and mir-83 by tests of ge- hr (Johnson et al. 1984). Embryos or starved L1’s were then netic suppression. mir-83(n4638); mir-34(gk437) double plated on HB101-seeded NGM plates and raised to adult- mutants display a defect in gonad morphogenesis. In addi- hood in the temperature scheme noted. Day one adults were tion, this defect reflects a loss of developmental robustness; paralyzed in 100 mM levamisole, mounted on 2% agarose the mir-83(n4638); mir-34(gk437) phenotype is signifi- pads, and scored using a Zeiss Axioskop differential inter- cantly enhanced in response to temperature changes but ference contrast (DIC) microscope and a 363 objective. A not by other environmental stresses that we tested. Based two-proportion z-test was used to determine significant dif- on our results, we conclude that mir-34 and mir-83 function ferences between counts except where triplicates are pre- together to help create or maintain robust function of the sented. In such cases mean values were compared using genetic network controlling gonad morphogenesis, such an unpaired t-test performed by PRISM. that the development of this important organ is protected Temperature oscillations from the temperature changes C.
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